Number of companies investing in Neuroscience drug … · Glossopharyngeal Neuralgia Guillain-Barre...

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1

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Neurological Disorders and Stroke

NINDS Office of Translational

Research: New Programs to

Support Therapy and Device Discovery and

Development

July 2015

Rajesh Ranganathan, PhD Director, Office of Translational Research

NINDS [email protected]

2

Number of companies investing in Neuroscience drug discovery

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2

3

Number of companies investing in Neuroscience drug discovery

4

CNS drug discovery portfolio

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5

6

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Ecosystem is pursuing new models – eliminate silos

Pharma

Biotech

Academia

Project 1Carsten Skarke and Garret A. FitzGerald, Science Translational Medicine April 2010

Project 2 Project 3

7

What should NINDS’s role be in this changing climate?

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FY 2011 FY 2012 FY 2013 FY2014 FY 2015

NINDS $1,622,003 $1,624,830 $1,533,795 $1,588,904 $1,604,607

NINDS % Change

Base 0.2% -5.6% 3.6% 1.0%

NIH $30,687,290 $30,860,387 $29,151,462 $30,150,853 $30,311,349

NIH % Change Base 0.6% -5.5% 3.4% 0.5%

� Average IC increase was 0.31%

� NINDS and NIMH each received increase of $12.3 M for BRAIN Initiative

� Funding up to 14th percentile

Appropriations (Dollars in Thousands)

9

Total NINDS Extramural Grants Budget

10

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

NIN

DS

Ext

ram

ura

l Gra

nt D

olla

rs (

in

Bill

ions)

NINDSExtramural

adjusted to 1995dollars

with ARRA

with ARRA--adjusted to 1995dollars

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6

5.274 5.344.887

0

1

2

3

4

5

6

7

Cancer Neurosciences Infectious Diseases

Do

llars

in B

illio

ns (

FY

20

13

)

FY 2013 Taxpayer Investment in Neuroscience

Now Exceeds Cancer

Research Category

Source: http://report.nih.gov/categorical_spending.aspx11

OTHER

10%

NIDDK

3%NIAAA

3%NCI

3%

NIGMS

3%

NHLBI

4%

NICHD

4%

NIDCD

4%

NIDA

8%

NEI

8%

NIA

8%

NIMH

15%

NINDS

27%

NIH Neuroscience Research

FIC 0.03%

TYPE 1 0.01%

NLM 0.02%

NCMHD 0.05%

NCATS 0.14%

NHGRI 0.26%

NIDCR 0.52%

NINR 0.52%

NIAMS 0.59%

NCCAM 0.60%

NIAID 1.06%

NIBIB 1.22%

NIEHS 1.50%

RMAP 1.64%

OD 2.14%

Other Includes:

Source: http://report.nih.gov/categorical_spending.aspx 12

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The Problem

Absence of the Septum Pellucidum Acquired Epileptiform Aphasia Acute Disseminated Encephalomyelitis ADHD Adrenoleukodystrophy Agenesis of the Corpus Callosum Agnosia Aicardi Syndrome AIDS - Neurological Complications Alexander Disease Alpers' Disease Alternating Hemiplegia Alzheimer's Disease Amyotrophic Lateral Sclerosis Anencephaly Aneurysm Angelman Syndrome Angiomatosis Anoxia Aphasia Arteriovenous Malformation Asperger Syndrome Ataxia Ataxia Telangiectasia Ataxias and Cerebellar/Spinocerebellar Degeneration Attention Deficit-Hyperactivity Disorder Autism Autonomic Dysfunction Back Pain Barth Syndrome Batten Disease Behcet's Disease Bell's Palsy Benign Essential Blepharospasm Benign Focal Amyotrophy Benign Intracranial Hypertension Bernhardt-Roth Syndrome Binswanger's Disease Blepharospasm Bloch-Sulzberger Syndrome Brachial Plexus Birth Injuries Brachial Plexus Injuries Bradbury-Eggleston Syndrome Brain and Spinal Tumors Brain Aneurysm Brain Injury Brown-Sequard Syndrome Bulbospinal Muscular Atrophy Canavan Disease Carpal Tunnel Syndrome Causalgia Cavernomas Cavernous Angioma Cavernous Malformation Central Cervical Cord Syndrome Central Cord Syndrome Central Pain Syndrome Cephalic Disorders Cerebellar Degeneration Cerebellar Hypoplasia Cerebral Aneurysm Cerebral Arteriosclerosis Cerebral Atrophy Cerebral Beriberi Cerebral Gigantism Cerebral Hypoxia Cerebral Palsy Cerebro-Oculo-Facio-Skeletal Syndrome Charcot-Marie-Tooth Disease Chiari Malformation Chorea Choreoacanthocytosis Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Chronic Orthostatic Intolerance Chronic Pain Cockayne Syndrome Type II Coffin Lowry Syndrome COFS Coma and Persistent Vegetative State Complex Regional Pain Syndrome Congenital Facial Diplegia Congenital Myasthenia Congenital Myopathy Congenital Vascular Cavernous Malformations Corticobasal Degeneration Cranial Arteritis Craniosynostosis Creutzfeldt-Jakob Disease Cumulative Trauma Disorders Cushing's Syndrome Cytomegalic Inclusion Body Disease (CIBD) Cytomegalovirus Infection Dancing Eyes-Dancing Feet Syndrome Dandy-Walker Syndrome Dawson Disease De Morsier's Syndrome Deep Brain Stimulation for Parkinson's Disease Dejerine-Klumpke Palsy Dementia - Multi-Infarct Dementia - Subcortical Dementia With Lewy Bodies Dentate Cerebellar Ataxia Dentatorubral Atrophy Dermatomyositis Developmental Dyspraxia Devic's Syndrome Diabetic Neuropathy Diffuse Sclerosis Dysautonomia Dysgraphia Dyslexia Dysphagia Dyspraxia Dyssynergia Cerebellaris Myoclonica Dyssynergia Cerebellaris Progressiva Dystonias Early Infantile Epileptic Encephalopathy Empty Sella Syndrome Encephalitis and Meningitis Encephalitis Lethargica Encephaloceles Encephalopathy Encephalotrigeminal Angiomatosis Epilepsy Erb-Duchenne and Dejerine-Klumpke Palsies Erb's Palsy Fabry's Disease Fahr's Syndrome Fainting Familial Dysautonomia Familial Hemangioma Familial Idiopathic Basal Ganglia Calcification Familial Periodic Paralyses Familial Spastic Paralysis Febrile Seizures Fisher Syndrome Floppy Infant Syndrome Friedreich's Ataxia Gaucher's Disease Gerstmann's Syndrome Gerstmann-Straussler-Scheinker Disease Giant Cell Arteritis Giant Cell Inclusion Disease

Globoid Cell Leukodystrophy Glossopharyngeal Neuralgia Guillain-Barre Syndrome Hallervorden-Spatz Disease Head Injury Headache Hemicrania Continua Hemifacial Spasm Hemiplegia Alterans Hereditary Neuropathies Hereditary Spastic Paraplegia Heredopathia Atactica Polyneuritiformis Herpes Zoster Herpes Zoster Oticus Hirayama Syndrome Holoprosencephaly HTLV-1 Associated Myelopathy Huntington's Disease Hydranencephaly Hydrocephalus Hydrocephalus - Normal Pressure Hydromyelia Hypercortisolism Hypersomnia Hypertonia Hypotonia - Infantile Hypoxia Immune-Mediated Encephalomyelitis Inclusion Body Myositis Incontinentia Pigmenti Infantile Hypotonia Infantile Phytanic Acid Storage Disease Infantile Refsum Disease Infantile Spasms Inflammatory Myopathy Intestinal Lipodystrophy Intracranial Cysts Intracranial Hypertension Isaac's Syndrome Joubert Syndrome Kearns-Sayre Syndrome Kennedy's Disease Kinsbourne syndrome Kleine-Levin Syndrome Klippel-Feil Syndrome Klippel-Trenaunay Syndrome (KTS) Klüver-Bucy Syndrome Korsakoff's Amnesic Syndrome Krabbe Disease Kugelberg-Welander Disease Kuru Lambert-Eaton Myasthenic Syndrome Landau-Kleffner Syndrome Lateral Femoral Cutaneous Nerve Entrapment Lateral Medullary Syndrome Learning Disabilities Leigh's Disease Lennox-Gastaut Syndrome Lesch-Nyhan Syndrome Leukodystrophy Levine-Critchley Syndrome Lewy Body Dementia Lipid Storage Diseases Lissencephaly Locked-In Syndrome Lou Gehrig's Disease Lupus - Neurological Sequelae Lyme Disease - Neurological Complications Machado-Joseph Disease Macrencephaly Megalencephaly Melkersson-Rosenthal Syndrome Meningitis Menkes Disease Meralgia Paresthetica

Metachromatic Leukodystrophy Microcephaly Migraine Miller Fisher Syndrome Mini-Strokes Mitochondrial Myopathies Mobius Syndrome Monomelic Amyotrophy Motor Neuron Diseases Moyamoya Disease Mucolipidoses Mucopolysaccharidoses Multifocal Motor Neuropathy Multi-Infarct Dementia Multiple Sclerosis Multiple System Atrophy Multiple System Atrophy with Orthostatic Hypotension Muscular Dystrophy Myasthenia - Congenital Myasthenia Gravis Myelinoclastic Diffuse Sclerosis Myoclonic Encephalopathy of Infants Myoclonus Myopathy Myopathy - Congenital Myopathy - Thyrotoxic Myotonia Myotonia Congenita Narcolepsy Neuroacanthocytosis Neurodegeneration with Brain Iron Accumulation Neurofibromatosis Neuroleptic Malignant Syndrome Neurological Complications of AIDS Neurological Complications Of Lyme Disease Neurological Manifestations of Pompe Disease Neurological Sequelae Of Lupus Neuromyelitis Optica Neuromyotonia Neuronal Ceroid Lipofuscinosis Neuronal Migration Disorders Neuropathy - Hereditary Neurosarcoidosis Neurotoxicity Nevus Cavernosus Niemann-Pick Disease Normal Pressure Hydrocephalus Occipital Neuralgia Occult Spinal Dysraphism Sequence Ohtahara Syndrome Olivopontocerebellar Atrophy Opsoclonus Myoclonus Orthostatic Hypotension O'Sullivan-McLeod Syndrome Overuse Syndrome Pain - Chronic Pantothenate Kinase-Associated Neurodegeneration Paraneoplastic Syndromes Paresthesia Parkinson's Disease Parmyotonia Congenita Paroxysmal Choreoathetosis Paroxysmal Hemicrania Parry-Romberg Pelizaeus-Merzbacher Disease Pena Shokeir II Syndrome Perineural Cysts Periodic Paralyses Peripheral Neuropathy Periventricular Leukomalacia Persistent Vegetative State Pervasive Developmental Disorders Phytanic Acid Storage Disease Pick's Disease

Pinched Nerve Piriformis Syndrome Pituitary Tumors Polymyositis Pompe Disease Porencephaly Postherpetic Neuralgia Postinfectious Encephalomyelitis Post-Polio Syndrome Postural Hypotension Postural Orthostatic Tachycardia Syndrome Postural achycardia Syndrome Primary Dentatum Atrophy Primary Lateral Sclerosis Prion Diseases Progressive Hemifacial Atrophy Progressive Locomotor Ataxia Progressive Multifocal Leukoencephalopathy Progressive Sclerosing Poliodystrophy Progressive Supranuclear Palsy Pseudotumor Cerebri Ramsay Hunt Syndrome Ramsay Hunt Syndrome I (formerly known as) Ramsay Hunt Syndrome II Rasmussen's Encephalitis Reflex Sympathetic Dystrophy Syndrome Refsum Disease Refsum Disease - Infantile Repetitive Motion Disorders Repetitive Stress Injuries Restless Legs Syndrome Retrovirus-Associated Myelopathy Rett Syndrome Reye's Syndrome Riley-Day Syndrome Sacral Nerve Root Cysts Saint Vitus Dance Salivary Gland Disease Sandhoff Disease Schilder's Disease Schizencephaly Seizure Disorder Septo-Optic Dysplasia Shaken Baby Syndrome Shingles Shy-Drager Syndrome Sjogren's Syndrome Sleep Apnea Sleeping Sickness Soto's Syndrome Spasticity Spina Bifida Spinal Cord Infarction Spinal Cord Injury Spinal Cord Tumors Spinal Muscular Atrophy Spinocerebellar Atrophy Spinocerebellar Degeneration Steele-Richardson-Olszewski Syndrome Stiff-Person Syndrome Striatonigral Degeneration Stroke Sturge-Weber Syndrome Subacute Sclerosing Panencephalitis Subcortical Arteriosclerotic Encephalopathy SUNCT Headache Swallowing Disorders Sydenham Chorea Syncope Syphilitic Spinal Sclerosis Syringohydromyelia Syringomyelia Systemic Lupus Erythematosus

Tabes Dorsalis Tardive Dyskinesia Tarlov Cysts Tay-Sachs Disease Temporal Arteritis Tethered Spinal Cord Syndrome Thomsen Disease Thoracic Outlet Syndrome Thyrotoxic Myopathy Tic Douloureux Todd's Paralysis Tourette Syndrome Transient Ischemic Attack Transmissible Spongiform Encephalopathies Transverse Myelitis Traumatic Brain Injury Tremor Trigeminal Neuralgia Tropical Spastic Paraparesis Tuberous Sclerosis Vascular Erectile Tumor Vasculitis including Temporal Arteritis Von Economo’s Disease Von Hippel-Lindau Disease (VHL) Von Recklinghausen's Disease Wallenberg's Syndrome Werdnig-Hoffman Disease Wernicke-Korsakoff Syndrome West Syndrome Whiplash Whipple's Disease Williams Syndrome Wilson's Disease X-Linked Spinal and Bulbar Muscular Atrophy Zellweger Syndrome

WWW.NINDS.NIH.GOV

Unmet need in hundreds of neurological disorders

1313

14

FY 2015 Appropriation Budget Distribution

1,385,870,

86.4%

159,498, 9.9%59,239, 3.7%

FY 2015 Budget Authority:

$1,604,607K

Extramural

Intramural

RMS

Dollars in Thousands

14

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Mission: To facilitate the preclinical discovery and development of new therapeutic interventions for neurological disorders

Bench

Preclinical

Patients

15

NINDS Office of Translational Research (OTR)

• Need to get therapeutics to humans (not bench to bookshelf)

o Develop translatable measures of PK/PD and target engagement

o Integrate clinical perspective

• Establish fail-early, fail-fast approach to portfolio management

o Milestone assessment critical to project progression

o Embrace early termination as success and learning opportunity

• Can’t do it alone – need partnerships and handoffs

o De-risk projects for downstream funding

o Actively facilitate partnership discussions

16

NINDS Translational Guiding Principles

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Anticonvulsant Screening Program (ASP)

CREATE Bio for Biotechnology Products and Biologics

Small Business Program: SBIR & STTR

Blueprint Neurotherapeutics (BPN 2.0) for Small Molecules

Countermeasures Against Chemical Threats (CounterACT)

CREATE Devices

Translational R21 (all modalities) / IGNITE

$47 M

$46 M

$19 M

$14 M

$10 M

$3.5 M

$2 M

IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises

17

NINDS uses a Variety of Translational Approaches

Discovery Preclinical Development Small Clinical Trials

NINDS Anticonvulsant Screening Program (ASP)

Approach: Provide services and expertise to investigators developing anticonvulsants

� Established in 1975 (Dr. Steve White: PI, Univ. of Utah)

� Screening performed via a contract mechanism using a battery of seizure models

� NINDS staff report results to participants, advise on future development

� Supplier IP protected; confidentiality maintained

� Role in 10 marketed drugs since 1990

18

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1850 1870 1890 1910 1930 1950 1970 1990 20100

5

10

15

20

25

30

35

40

Bromide

PhenobarbitalPhenytoin

AcetazolamideTrimethadione

MephenytoinParamethadioneCorticosteroids/ACTHPhenacemidePhensuximidePrimidone

MethsuximideEthotoinEthosuximide

ChlordiazepoxideSulthiameDiazepam

CarbamazepineValproate

ClonazepamClobazam Progabide

VigabatrinZonisamideLamotrigineOxcarbazepine

FelbamateGabapentinTopiramateTiagabine

LevetiracetamPregabalin

StiripentolRufinamideLacosamideEslicarbazepine acetate

First generation

Second generation

Third generation

Mephobarbital

Retigabine (ezogabine)Perampanel

Year of introduction

Nu

mb

er

of

AE

Ds

Imepitoin (dogs)

Start of ASP

Adapted from Loscher & Schmidt, 2011, Epilepsia, 52:657

History of Antiepileptic Drugs (AEDs)

ASP Mission: To encourage and facilitate the discovery of new therapeutic agents for epilepsy

19

Nu

mb

er

of

AE

Ds

2

0

6

4

10

8

14

12

18

16

= ASP Contribution

= Major contribution

Year of introduction

*

*

*

**

*Start

of ASP

History of Antiepileptic Drugs (AEDs)

20

Adapted from Loscher & Schmidt, 2011, Epilepsia, 52:657

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CREATE Devices


$47 M

$46 M

$19 M

$14 M

$10 M

$3.5 M

$2 M


21



Cooperative Program Purpose and Goals

• Program launched in 2002 and includes drugs, biologics, and devices

• Purpose: To stimulate preclinical development of therapeutics in non-profit and small business sectors

• Features: Special review, milestone-based decisions

22

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Portfolio (n=80) by Indication (2002-2014)

23

Other:

Batten disease

Down Syndrome

Neurodegeneration

Neurofibroma

Insecticide poisoning

Peripheral nerve injury

Phenylketonuria

SMA

Spinal and Bulbar Muscular Atrophy

14% 14%

13%

7% 7% 7%

6% 6%6%

4%4%

3% 3% 3%3%

0

2

4

6

8

10

12

# P

roje

cts

Portfolio (n=80) by Interventional Modality (2002-2014)

24

Other:

Vaccine

Dog Center

Drug Discovery Center

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Translational R21 by Indication 2014 (n=54)

25

Other: Arteriovenous Malformation, CIDP, Guillain-Barre Syndrome, HIV, Huntington's,

Neonatal Encephalopathy, Nerve Injury, Neurodegenerative Diseases, Neurofibromatosis,

Neuropathy, Parkinson's, PSP, Rett's Syndrome, Spinocerebellar Ataxia, TBI

13%

11%

9%

9%

7%5%4%

4%4%

4%

30%

Muscular DystrophyStrokeLysosomal StorageEpilepsySMATumorsALSAlzheimer'sMultiple SclerosisSleep DisordersOther

• At least 8 projects have graduated to clinical trials

– 80+ projects actively managed in 10+ years

• Progressive strengthening of peer-review and milestone assessments

– 15 discontinuations for not meeting milestones

• In 2014, at least 5 INDs were filed: • a small molecule in Alzheimer’s Disease;

• a gene therapy in Glioblastoma;

• gene therapy and antisense oligos in Muscular Dystrophy

26

Achievements of the Legacy Program

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Case Study #1

• PK to determine treatment regimen

• Improve mitochondrial function in animals

Year 01 Year 02 Year 03

• Demonstrate motor and sensory recovery

• pre-IND meeting

Year 04

• Demonstrate recovery in a severe SCI model in either gender

Efficacy criteria

not fully met in

either gender

$$ awarded

4 month NCE to address differences in injury severityAnd ultimately discontinued

• Submit IND

Mitochondrial inhibitor to treat acute spinal cord injury (SCI)

27

Case Study #2

• Demonstrate efficacy in LINCL KO mice

• Increase functional enzyme levels in NHP

Year 01 Year 02 Year 03

• pre-IND meeting• Manufacture

vector

Year 04 Year 05

• Assess anti-vector immunity

• Met criteria for

enzyme

expression

• Met efficacy criteria in KO mice

• Pre-IND meeting held Yr 2

• Advance NHP milestone Yr 3

$$ awarded $$ awardedModified milestones$$ awarded

$$ awarded

• Passed vector

lot release

criteria

• Met functional

enzyme criteria

in NHP

• No toxicity in NHP

• Received IRB approval

• IND submitted in Yr 4

Modified milestonesDelayed funding until IND feedback.Reduced budget

• biodistribution study and IND-enabling toxicity studies in rat and NHP

• IRB, RAC submissions

Gene therapy to treat Batten Disease / late infantile neuronal ceroid lipofuscinosis (LINCL)

• Submit IND

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29

Translating a CSF delivered AAV9-SMN for treatment of Spinal Muscular Atrophy

• Tailored approach: Cater to the various modalities

• Transitions: Reduce delay between funding mechanisms

• Risk management: More points for attrition

• Due Diligence: Implement RIGOR guidelines; increase progress review

frequency

• Flexibility: Access to contracts and consultants; project entry at various

points; supplements to address unanticipated needs

30

Opportunities for Further Enhancement

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Cooperative Research to Enable and Advance Translational Enterprises (CREATE)

CREATE Bio ProgramModality: Biologics/Biotechnology ProductsPurpose

• Discovery: Optimization of therapeutic leads

• Development: IND-enabling studies/Early phase clinical trials

End Goals• Discovery: Characterize and select a lead

candidate• Development: Submit an IND application

Funding to advance potential therapeutics (biologics or devices)into clinical development

31

CREATE Bio Program

Animal POC

Lead Optimization

IND Enabling Studies

Small Clinical Trials Clinical POC

U01

PreparatoryUH2

IND Enabling

UH3

Small Clinical TrialsUH3 (optional)

Candidate

Leads

IND

Early Clinical Development Asset

Development Track

Discovery Track

Discovery Track (U01) Development Track (UH2/UH3)

Budget per year <$0.5 M year < $1- 1.5 M

Duration Up to 4 years Up to 5 years

32

Next Application Date: August 11, 2015

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Cooperative Research to Enable and Advance Translational Enterprises (CREATE)

CREATE Devices ProgramModality: Therapeutic Devices

• Informing Device Design: Pre-clinical/clinical studies to inform final device design

• 510(k) Market Approval: Pre-clinical/clinical studies leading to a 510(k)/510(k) De Novo submission

• PMA or HDE*: Pre-clinical/early clinical studies leading to a full Feasibility Study/Pivotal Trial in support of a PMA/HDE

Funding to advance potential therapeutics (biologics or devices)into clinical development

33

*Pre-Market Approval (PMA) or Humanitarian Device Exemption (HDE)

510(k) Market Approval

PMA or HDE

FDA Pre-SubmissionGuidance

Informing Device Design Clinical Study (UH3/U44-II)

Pre-Clinical (UH2/U44-I)

CREATE Devices

Pre-Clinical(UH2/U44-I)

Pre-Clinical(UH2/U44-I)

Clinical Study (UH3/U44-II)

Optional Clinical Study

(UH3/U44-II)

UH2/U44-I UH3/U44-II

Budget per year <$1 M <$1.5 M

Duration Up to 3 years Up to 4 years

Budget total <$3 M <$6 M

34

FDA Submission

Pre-Clinical(UH3/U44-II)


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CREATE Devices


$47 M

$46 M

$19 M

$14 M

$10 M

$3.5 M

$2 M


35



Blueprint Neurotherapeutics Network (BPN)

36

Combining strengths of NIH and industry for small molecule therapeutics

BPN ProgramModality: Small Molecule

• Discovery: Hit-to-lead and lead optimization• Development: Formulation, scale up and

manufacture, IND-enabling studies, and first-in-man clinical trials

End Goals• Discovery: Characterize and select a preclinical

candidate• Development: Complete IND-enabling studies, file

an IND and complete first-in-man trial• Advance projects for hand-off

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Lead Development Team

Principal Investigator*Industry-seasoned consultants

NIH staff

Bioactivity/EfficacyStudies

PK/Tox

Phase IClinicalTrials

DataManagement

Formulation/Manufacturing

Blueprint Neurotherapeutics Network Offering Infrastructure, Expertise, and Funding

*PI retains

intellectual property

MedicinalChemistry

3737

BPN Consultants

• Assay development, pharmacology

– Lisa Minor – Bill Martin– Jeff Conn

• Medicinal chemistry– Graham Johnson– Donna Romero– Neil Moss– Paul C. Anderson– Steve Young– John McCall

• DMPK– Paul Pearson– Jiunn Lin– Ron White– Ron Franklin

• Toxicology– Marc Bailie– Steve Duddy– Gary Wolfe

• Development– Peter Farina– Mike Detke– Cristina Csimma– Gian Luca Araldi– Jon P. Lawson– John M. “Jay” Sisco

• Upcoming– Regulatory affairs, Phase I Clinical

Pharmacology, Medical Writing, & Business Development

See bios at http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm3838

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Pre-clinical safety testing

Exploratory Studies

Optimization Chemistry

Human safety testing (Phase I)

New drug candidates

licensed

Projects Launched

Validated AssaysEmerging SAR

Milestones

Projects are Milestone-DrivenExternal Review Committee Assesses Progress Biannually

High attrition

rate anticipated

External Oversight Committee

Peter Farina, PhD (chair)Jeffrey Conn, PhDMichael J. Detke, MD, PhDJohn McCall, PhD Cristina Csimma, PhD

3939

Who Applies for BPN?

• Researchers who are new to drug discovery

• Researchers who are experienced in drug discovery but lack necessary research facilities

• Academic labs and small businesses

4040

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15 Projects Initiated 2011- 2013

Principal Investigator Institution Disorder

Mark Gurney Tetra Discovery Partners Alzheimer’s

Susan Slaugenhaupt Mass. General Hospital Familial Dysautonomia

Paul Kenny Eolas Therapeutics Smoking Cessation

Steven Wagner UC San Diego Alzheimer’s

Konstantin Petrukhin Columbia University/iCura Macular Degeneration

Kirill Ostanin Navigen Macular Degeneration

Paul Humphries Reset Therapeutics Narcolepsy

George Maynard Axerion Alzheimer’s

John Bixby University of Miami Optic Neuropathy

Raymond Dingledine Emory University Stroke

Marcie Glicksman Brigham and Women’s Hospital ALS

Michael Lark Trevena Depression

Al Robichaud Sage Therapeutics Fragile X

Edwin Rubel University of Washington Hearing Loss

D. James Surmeier Northwestern University Parkinson’s

Dis

co

ntin

ued

See abstracts at http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm4141

Advance Projects for Hand-Off

Exploratory/Hit to Lead

Lead Optimization

Scale up & Manufacturing

IND Enabling

Phase I

Entry:

•Strong science

•BPN mission

Exit:

• External funding/ partnership

• Other grants

• Attrition

Decreases risk as projects successfully advance development stages

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Facilitated licensing of drug candidates:

• Macular degeneration drug candidate licensed to iCura

• New drug for mild cognitive impairment led to investment by Johnson & Johnson to project’s industry partner, Tetra Discovery Partners

• Orexin-1 receptor antagonist as a tobacco addiction treatment licensed to Eolas, who just signed an agreement with Astra Zeneca

BPN Recent Successes

4343

What’s New in BPN 2016-2020

• Flexibility in mix of contract access and grant support

– Investigators choose what combination best fits their needs

– Offers option for grant-only support

• Flexibility in entry point

– Projects can enter during Discovery or Development

• Phased funding allows for due diligence, filling in data gaps

• SBIR track available

4444

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Projects Can Enter at Any Preclinical Stage

45

PreparatoryPhase

• Complete entry criteria for SAR or IND-enabling studies

• Conduct due diligence

Discovery Development

Hit to LeadLead

OptimizationIND Enabling Phase I Trial

All Projects Begin with Preparatory Phase

General (UH2/UH3)UH2: Up to $300K direct costs x 1 yearUH3: Up to $1.5M/year direct costs x 4 years

SBIR (U44-I/II)Phase I: Up to $400K total costs x 1 yearPhase II: Up to $4M total across 3 years


• PAR-14-293 for all applicants

• PAR-14-292 for small businesses (SBIR)

• Next applications due Aug. 11, 2015

• Peer review in Dec. 2015 (special review panel)

• Grants awarded Jan. 2016

• For the following indications

• Psychiatric disorders

• Neurological disorders

• Degenerative dementias of aging

• Developmental disorders

• Chronic pain conditions

• Alcohol dependence

• Drug addiction

46

Now Accepting New Applications

46

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CREATE Devices


$47 M

$46 M

$19 M

$14 M

$10 M

$3.5 M

$2 M


47



Small Business Program Overview

• Congressionally mandated set-aside programs

• R&D with potential for commercialization

• ~$46M in FY2015 (3.3% of the extramural budget)

• Broad scope

• Neurotherapeutics, diagnostics, and tools for neuroscience research

• Bench research, translational research, and early stage clinical trials

48

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Three Phase Program

• Phase I – Feasibility Study– $225K for up to 2 years– ($700K if a waiver topic)

• Phase II – Full Research/R&D– $1.5M for up to 3 years– ($3M if a waiver topic)

• Phase IIB– Full Research/R&D– $1M/yr for up to 3 years

• Phase III– Commercialization Stage– Use of non-SBIR/STTR funds

49

Applicants should propose a budget that is reasonable and appropriate for completion of the research project.

Please contact us for guidance.

Small Businesses by Modality

50

19%

21%

18%

20%

19%

3%

2014

diagnostic

biologic

small molecule

tool

therapeutic device

other

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Lift Labs funded by SBIR to develop a spoon or fork attachment that cancels out hand tremor. Company acquired by Google in 2014.

SBIR Recent Success

http://www.google.com/liftware/

51

Additional Pipeline Needs to be Addressed

52

Basic scienceCREATE/BPN 2.0

In Vitro

Assays

Animal

models

Tools

PD Markers

Technology

Rigorous

POC

Bioactive

Compounds

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Innovation Grants to Nurture Initial Translational Efforts (IGNITE)

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1. Establish essential assays (in vitro and in vivo) to identify and optimize bioactive leads(s)

2. Characterize bioactive lead(s)

3. Deliver in vivo efficacy data using clinically relevant outcome measures and/or in vivo target engagement

Proposed Feeder Programs for Translational Pipeline

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IGNITE (Assay Development)

IGNITE (PD & Efficacy)

IGNITE (Animal Model Dev.)

IGNITE (Platform Technology)

CREATE Devices

Launch Dec. 2014: Next receipt date Jun. 2015

Launch Dec. 2014: Next receipt date Jun. 2015

Launch late 2015

Launch 2016

IGNITE: Innovation Grants to Nurture Initial Translational Efforts


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Execution Phase

PAR-15-070: Hit identification: screening, physicochemical characterization, in vitro pharmacological characterization

PAR-15-071: Pharmacodynamic, in vivo characterization of compound(s)

IGNITE

R33

R21

R21 R33

Budget per year < $0.25M < $0.5M

Duration No more than 2 years No more than 2 years

Budget total

(R21/R33)<0.75M for Entire 3 Year Period

Planning/Development Phase

PAR-15-070: Assay Development and Validation

PAR-15-071: Further compound characterization including pharmacokinetic studies and planning for in vivo and pharmacodynamic studies

�� Meet Milestones

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IGNITE Key Advantages

• Provides funding to seamlessly advance projects from the early discovery stage into late-stage translational funding programs

• Encourages investigators to clearly focus on stage-specific drug discovery goals and allows the time to do so

• Encourages:

1. Characterization of therapeutic agents

2. Planning, set up, and validation of testing paradigms and models

3. Employment of RIGOR guidance

4. Partnerships between academics and industry

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CREATE Devices


$47 M

$45 M

$19 M

$14 M

$10 M

$3.5 M

$2 M


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Mission:To develop FDA-approved therapeutics and diagnostic

technologies that will reduce mortality and morbidity during and

after chemical emergency events.

NIH CounterACTCountermeasures Against Chemical Threats

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Biological (~$1.7B)

•Category A, B, C

•Bacterial, e.g., anthrax

•Viral, e.g., small pox

•Toxins, e.g., botulinum

Radiation/Nuclear (~$46M)

•Bomb detonation

•Radiation Dispersal Device

•Attack on n. reactor

or on spent fuels

NIAID Oversight

NIAID Management

NIH Biodefense Program

Chemical (~$47M)

•Neurological, e.g., WMDs, sarin,

pesticides

•Pulmonary, e.g., chlorine, phosgene

•Metabolic, e.g., cyanide, H2S

•Vesicants, e.g., arsenicals

NINDS Management

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Chemical Warfare� World War I and II: thousands of fatalities

� Iran-Iraq War (1980-88): thousands of fatalities

� Current conflicts in the Middle East: thousands of fatalities

Terrorism/Non-military malicious use� Tokyo Subway Attacks (1995): thousands affected; 12 dead

� Jonestown mass suicide (1978): 900 dead

� Tylenol and Excedrin poisonings (1980’s): few fatalities

Industrial Accidents� Occur Daily; thousands of injuries and fatalities annually

� Dupont Corp. (WV – 2010): 3 Phosgene releases in 1

week

� Bhopal Union Carbide disaster (1984): 5,000 fatalities from

Methyl Isocyanate

General Poisonings� 2.2 million calls to Poison Control Centers in 2012 alone

� Brodifacoum, Pesticides

Burden of Illness

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MissionThe mission of the NIH CounterACT Program is to understand

fundamental mechanisms of toxicity caused by chemical threat

agents and the application of this knowledge to develop promising

therapeutics for reducing mortality and morbidity caused by these

agents.

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Chemical Classes

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TranslationalBasic

Assay

DevelopmentTarget ID

Clinical

Trials

Proof

of

Principle

Pre-IND/IDE

Studies

Clinical

Optimization/

Preclinical

EfficacyScreening

NIH BARDA

Over 30+ “hits” and/or targets identified

NeuregulinBrovana*RolipramSulfanegenGalantamine*LY293558AEOL 10150 (M)Doxycycline*

Cobinamide (M) Midazolam*

* Denotes FDA-approved

compound for another indication

Drug indication:

Black = Vesicants

Red = Nerve Agents

Blue = Pulmonary Agents

Green = Cyanide

(M) = multiple indications

Products in the Pipeline

*BARDA: Biomedical Advanced Research & Development Authority

Advice for Preparing an Application

• Contact NIH staff

- Confirm which entry stage is best fit

- Discuss activities for Preparatory Phase

- Applications $500K+ must be preapproved to submit

• Read the FOAs (these are not typical NIH application)

• Show the data for assay validation, target validation, etc.

Review FAQs at program websites

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Prepare a robustness

data package

Keep the end in mind …

Target Product Profile (TPP)

Initial plans for clinical POC

trial

Address IP Strategy

Have multidisciplinary

team to formulate the

plans

Know the review

environment-NINDS

review

Propose rigorous

experiments with clear

milestones for success

and go/no-goTalk to NINDS Program

Staff

Check out FAQs,

examples, and resources

in the NINDS program

website

Rigorous Study Design and

Reporting

Plan ahead

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Planning Essentials

Talk to NINDS Program

Staff

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Planning Essentials

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John Kehne, Ph.D.Program Director

Hao Wang, Ph.D.Program Director

Rajesh Ranganathan, Ph.D. Director

Linda McGavern, Ph.D.Scientific Project Manager

Stephanie Fertig, MBADirector, Small Business Program

Amir Tamiz, Ph.D.Program Director

Charles Cywin, Ph.D.Scientific Project Manager

Shamsi Raeissi, Ph.DScientific Project Manager

Chris Boshoff, Ph.D.Scientific Project Manager

Mary Ann Pelleymounter,

Ph.D.Program Director

Medical Director (1 Vacancy)

Dave Yeung, Ph.D.Scientific Project Manager

David A. Jett, Ph.D.Program Director

Pascal Laeng, Ph.D.Scientific Project Manager

Brian Klein, Ph.D.Scientific Project Manager

Questions?

[email protected]

http://www.ninds.nih.gov/otr

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